Fallen Angel Drugs - Optimization Results

Generated: 2025-11-17 00:31:43

Total Drugs Analyzed: 23

Slide 1: Tarenflurbil (Flurizan)

Initial Task: BBBP

SMILES: C[C@H](C1=CC(=C(C=C1)C2=CC=CC=C2)F)C(=O)O

❌ Optimization Failed for Tarenflurbil (Flurizan)

No valid paths found. The optimization could not generate any improved molecules.

📊 Initial Molecule Scores

Input SMILES: C[C@H](C1=CC(=C(C=C1)C2=CC=CC=C2)F)C(=O)O

Reason: All generated molecules had worse scores than the initial molecule.

🔧 Recommendations

  1. Increase beams: Try num_beams=7 or num_beams=10 for more diversity
  2. Change initial task: Try a different task as the starting point
  3. Reduce depth: Start with depth=1 to see if single-step improvements work
  4. Check initial molecule: It may already be highly optimized

Slide 2: Gavestinel (GV-150,526)

Initial Task: BBBP

SMILES: C1=CC=C(C=C1)NC(=O)/C=C/C2=C(C(=O)O)NC3=C2C(=CC(=C3)Cl)Cl

❌ Optimization Failed for Gavestinel (GV-150,526)

No valid paths found. The optimization could not generate any improved molecules.

📊 Initial Molecule Scores

Input SMILES: C1=CC=C(C=C1)NC(=O)/C=C/C2=C(C(=O)O)NC3=C2C(=CC(=C3)Cl)Cl

Reason: All generated molecules had worse scores than the initial molecule.

🔧 Recommendations

  1. Increase beams: Try num_beams=7 or num_beams=10 for more diversity
  2. Change initial task: Try a different task as the starting point
  3. Reduce depth: Start with depth=1 to see if single-step improvements work
  4. Check initial molecule: It may already be highly optimized

Slide 3: NXY-059 (Cerovive)

Initial Task: BBBP

SMILES: CC(C)(C)/[N+](=C/C1=CC=C(C=C1S(=O)(=O)OC)S(=O)(=O)OC)/[O-]

❌ Optimization Failed for NXY-059 (Cerovive)

No valid paths found. The optimization could not generate any improved molecules.

📊 Initial Molecule Scores

Input SMILES: CC(C)(C)/[N+](=C/C1=CC=C(C=C1S(=O)(=O)OC)S(=O)(=O)OC)/[O-]

Reason: All generated molecules had worse scores than the initial molecule.

🔧 Recommendations

  1. Increase beams: Try num_beams=7 or num_beams=10 for more diversity
  2. Change initial task: Try a different task as the starting point
  3. Reduce depth: Start with depth=1 to see if single-step improvements work
  4. Check initial molecule: It may already be highly optimized

Slide 4: PF-03758309 (PF-3758309)

Initial Task: HIA

SMILES: CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C(=O)N[C@H](CN(C)C)C5=CC=CC=C5)C4(C)C)SC=C2

PF-03758309 (PF-3758309) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C(=O)N[C@H](CN(C)C)C5=CC=CC=C5)C4(C)C)SC=C2`
**QED (Drug-likeness):** 0.3671 **Number of Blocks:** 4
▶ Show ADMET Scores
Task Score
AMES 0.419049
BBBP 0.778013
CYP3A4 0.011948
DILI 0.793920
HIA 0.984575
PGP 0.499705
**Final Optimized** `COc1cc(-c2n[nH]c3c2CN(c2n[nH]c4c2CN(c2n[nH]c5c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc6ccsc26)C5(C)C)C4(C)C)C3(C)C)ccc1O`
**QED (Drug-likeness):** 0.0961 (-0.2710) ❌ **Number of Blocks:** 6 (+2) ↑ **Total Block Changes:** 13
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%

Optimization Steps:

DETAILSPLACEHOLDER2

After (Step 1)

Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1

QED: 0.2053 (-0.1618) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 6 (+3, -3)

HIA Score: 0.984575 → 0.995240 (+0.010665)

DETAILSPLACEHOLDER3

▶ Step 2: PGP (+0.0081 ↓) ➡️
**Before (Step 1)** `Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1`
**QED:** 0.2053 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.717762 ↓ lower
BBBP 0.000191 ↑ higher
CYP3A4 0.003685 ↓ lower
DILI 0.691250 ↓ lower
HIA 0.995240 ↑ higher
PGP 0.564487 ↓ lower
**After (Step 2)** `Cc1nc(N[C@H](CN(C)C)NC(=O)N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)c2sccc2n1`

QED: 0.1259 (-0.0794) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 3 (+2, -1)

PGP Score: 0.564487 → 0.572543 (+0.008057)

DETAILSPLACEHOLDER5

DETAILSPLACEHOLDER6

After (Step 3)

COc1cc(-c2n[nH]c3c2CN(c2n[nH]c4c2CN(c2n[nH]c5c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc6ccsc26)C5(C)C)C4(C)C)C3(C)C)ccc1O

QED: 0.0961 (-0.0299) ❌

Number of Blocks: 6 (+1) ↑

Block Changes: 4 (+2, -2)

CYP3A4 Score: 0.004173 → 0.000889 (-0.003285)

DETAILSPLACEHOLDER7

📊 Step Details

Step 1: HIA ✅

Original New Change
0.984575 0.995240 +0.010665 ↑ 
Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1

Step 2: PGP ⚠️

Original New Change
0.564487 0.572543 +0.008057 ↓ 
Cc1nc(N[C@H](CN(C)C)NC(=O)N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)c2sccc2n1

Step 3: CYP3A4 ✅

Original New Change
0.004173 0.000889 -0.003285 ↓ 
COc1cc(-c2n[nH]c3c2CN(c2n[nH]c4c2CN(c2n[nH]c5c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc6ccsc26)C5(C)C)C4(C)C)C3(C)C)ccc1O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.419049 0.686654 +0.267605 -0.6386 +63.86% ❌ Declined
BBBP ↑ higher 0.778013 0.000213 -0.777801 -0.9997 -99.97% ❌ Declined
CYP3A4 ↓ lower 0.011948 0.000889 -0.011059 +0.9256 -92.56% ✅ Improved
DILI ↓ lower 0.793920 0.659112 -0.134808 +0.1698 -16.98% ✅ Improved
HIA ↑ higher 0.984575 0.997891 +0.013316 +0.0135 +1.35% ✅ Improved
PGP ↓ lower 0.499705 0.556859 +0.057154 -0.1144 +11.44% ❌ Declined

Improved: 3/6 (50.0%) | Molecules: 139 | Paths: 2743

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0002 ↑ 0.5 0.4998
AMES 0.6867 ↓ 0.3 0.3867
DILI 0.6591 ↓ 0.4 0.2591
PGP 0.5569 ↓ 0.3 0.2569

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0009 ↓ 0.55
HIA 0.9979 ↑ 0.2

Slide 5: Olcegepant (BIBN-4096BS)

Initial Task: HIA

SMILES: C1=CC2=C(C=C1)NC(=O)N(C2)C3CCN(CC3)C(=O)N[C@H](CC4=CC(=C(C(=C4)Br)O)Br)C(=O)N[C@@H](CCCCN)C(=O)N5CCN(CC5)C6=CC=NC=C6

Olcegepant (BIBN-4096BS) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `C1=CC2=C(C=C1)NC(=O)N(C2)C3CCN(CC3)C(=O)N[C@H](CC4=CC(=C(C(=C4)Br)O)Br)C(=O)N[C@@H](CCCCN)C(=O)N5CCN(CC5)C6=CC=NC=C6`
**QED (Drug-likeness):** 0.1666 **Number of Blocks:** 5
▶ Show ADMET Scores
Task Score
AMES 0.721609
BBBP 0.000066
CYP3A4 0.009376
DILI 0.714050
HIA 0.989571
PGP 0.702944
**Final Optimized** `CC1(C)c2[nH]nc(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)N3Cc4c(N[C@H](Cc5cc(Br)c(O)c(Br)c5)C(=O)C(=O)/C=C/c5c(C(=O)O)[nH]c6cc(Cl)cc(Cl)c56)n[nH]c4C3(C)C)c2CN1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1`
**QED (Drug-likeness):** 0.0265 (-0.1401) ❌ **Number of Blocks:** 7 (+2) ↑ **Total Block Changes:** 16
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ✅ 0.528857 -0.192753 +0.2671 -26.71%
BBBP ✅ 0.000205 +0.000139 +2.1037 +210.37%
CYP3A4 ✅ 0.000009 -0.009367 +0.9991 -99.91%
DILI ✅ 0.525996 -0.188054 +0.2634 -26.34%
HIA ✅ 0.999984 +0.010413 +0.0105 +1.05%
PGP ❌ 0.824368 +0.121425 -0.1727 +17.27%

Optimization Steps:

DETAILSPLACEHOLDER10

After (Step 1)

CC(C)CCOc1n[nH]c2c1CN(C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2(C)C

QED: 0.0420 (-0.1246) ❌

Number of Blocks: 6 (+1) ↑

Block Changes: 8 (+4, -4)

HIA Score: 0.989571 → 0.999710 (+0.010140)

DETAILSPLACEHOLDER11

DETAILSPLACEHOLDER12

After (Step 2)

CCCCC(CC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2(C)C

QED: 0.0182 (-0.0238) ❌

Number of Blocks: 7 (+1) ↑

Block Changes: 3 (+2, -1)

AMES Score: 0.612386 → 0.564568 (-0.047817)

DETAILSPLACEHOLDER13

DETAILSPLACEHOLDER14

After (Step 3)

CC1(C)c2[nH]nc(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)N3Cc4c(N[C@H](Cc5cc(Br)c(O)c(Br)c5)C(=O)C(=O)/C=C/c5c(C(=O)O)[nH]c6cc(Cl)cc(Cl)c56)n[nH]c4C3(C)C)c2CN1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

QED: 0.0265 (+0.0083) ✅

Number of Blocks: 7 (+0) ➡️

Block Changes: 5 (+2, -3)

CYP3A4 Score: 0.000019 → 0.000009 (-0.000011)

DETAILSPLACEHOLDER15

📊 Step Details

Step 1: HIA ✅

Original New Change
0.989571 0.999710 +0.010140 ↑ 
CC(C)CCOc1n[nH]c2c1CN(C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2(C)C

Step 2: AMES ✅

Original New Change
0.612386 0.564568 -0.047817 ↓ 
CCCCC(CC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2(C)C

Step 3: CYP3A4 ✅

Original New Change
0.000019 0.000009 -0.000011 ↓ 
CC1(C)c2[nH]nc(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)N3Cc4c(N[C@H](Cc5cc(Br)c(O)c(Br)c5)C(=O)C(=O)/C=C/c5c(C(=O)O)[nH]c6cc(Cl)cc(Cl)c56)n[nH]c4C3(C)C)c2CN1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.721609 0.528857 -0.192753 +0.2671 -26.71% ✅ Improved
BBBP ↑ higher 0.000066 0.000205 +0.000139 +2.1037 +210.37% ✅ Improved
CYP3A4 ↓ lower 0.009376 0.000009 -0.009367 +0.9991 -99.91% ✅ Improved
DILI ↓ lower 0.714050 0.525996 -0.188054 +0.2634 -26.34% ✅ Improved
HIA ↑ higher 0.989571 0.999984 +0.010413 +0.0105 +1.05% ✅ Improved
PGP ↓ lower 0.702944 0.824368 +0.121425 -0.1727 +17.27% ❌ Declined

Improved: 5/6 (83.3%) | Molecules: 637 | Paths: 5011

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
PGP 0.8244 ↓ 0.3 0.5244
BBBP 0.0002 ↑ 0.5 0.4998
AMES 0.5289 ↓ 0.3 0.2289
DILI 0.5260 ↓ 0.4 0.1260

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0000 ↓ 0.55
HIA 1.0000 ↑ 0.2

Slide 6: EPI-506 (ralaniten acetate / prodrug of EPI-002)

Initial Task: HIA

SMILES: CC(=O)OC[C@H](COC1=CC=C(C=C1)C(C)(C)C2=CC=C(C=C2)OC[C@@H](CCl)OC(=O)C)OC(=O)C

❌ Optimization Failed for EPI-506 (ralaniten acetate / prodrug of EPI-002)

No valid paths found. The optimization could not generate any improved molecules.

📊 Initial Molecule Scores

Input SMILES: CC(=O)OC[C@H](COC1=CC=C(C=C1)C(C)(C)C2=CC=C(C=C2)OC[C@@H](CCl)OC(=O)C)OC(=O)C

Reason: All generated molecules had worse scores than the initial molecule.

🔧 Recommendations

  1. Increase beams: Try num_beams=7 or num_beams=10 for more diversity
  2. Change initial task: Try a different task as the starting point
  3. Reduce depth: Start with depth=1 to see if single-step improvements work
  4. Check initial molecule: It may already be highly optimized

Slide 7: KPT-9274

Initial Task: HIA

SMILES: C1=CC(=NC=C1/C=C/C(=O)NCC2=CC3=C(C(=CC(=C3)C4=CC=C(C=C4)C(=O)N5CCC(CC5)(F)F)C6=CC=C(C=C6)F)O2)N

KPT-9274 - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `C1=CC(=NC=C1/C=C/C(=O)NCC2=CC3=C(C(=CC(=C3)C4=CC=C(C=C4)C(=O)N5CCC(CC5)(F)F)C6=CC=C(C=C6)F)O2)N`
**QED (Drug-likeness):** 0.1918 **Number of Blocks:** 4
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
6 		**Final Optimized** `CC(=O)OC[C@H](CON1Cc2c(-c3cn(C)c4ccccc34)n[nH]c2C1(C)C)OC(C)=O`
**QED (Drug-likeness):** 0.5639 (+0.3721) ✅ **Number of Blocks:** 2 (-2) ↓ **Total Block Changes:** 16
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
7

Optimization Steps:

DETAILSPLACEHOLDER18

After (Step 1)

CC(=O)OC[C@H](CONCc1cc2cc(-c3ccc(C(C)(C)c4ccc(N5CCC(F)(F)CC5)cc4)cc3)cc(-c3ccc(F)cc3)c2o1)OC(C)=O

QED: 0.0731 (-0.1188) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 6 (+3, -3)

HIA Score: 0.988937 → 0.941353 (-0.047584)

DETAILSPLACEHOLDER19

DETAILSPLACEHOLDER20

After (Step 2)

CC(=O)OC[C@H](COC(=O)/C=C/c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)OC(C)=O

QED: 0.3503 (+0.2772) ✅

Number of Blocks: 2 (-2) ↓

Block Changes: 6 (+2, -4)

AMES Score: 0.432780 → 0.408373 (-0.024407)

DETAILSPLACEHOLDER21

DETAILSPLACEHOLDER22

After (Step 3)

CC(=O)OC[C@H](CON1Cc2c(-c3cn(C)c4ccccc34)n[nH]c2C1(C)C)OC(C)=O

QED: 0.5639 (+0.2137) ✅

Number of Blocks: 2 (+0) ➡️

Block Changes: 4 (+2, -2)

AMES Score: 0.408373 → 0.381034 (-0.027339)

DETAILSPLACEHOLDER23

📊 Step Details

Step 1: HIA ⚠️

Original New Change
0.988937 0.941353 -0.047584 ↑ 
CC(=O)OC[C@H](CONCc1cc2cc(-c3ccc(C(C)(C)c4ccc(N5CCC(F)(F)CC5)cc4)cc3)cc(-c3ccc(F)cc3)c2o1)OC(C)=O

Step 2: AMES ✅

Original New Change
0.432780 0.408373 -0.024407 ↓ 
CC(=O)OC[C@H](COC(=O)/C=C/c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)OC(C)=O

Step 3: AMES ✅

Original New Change
0.408373 0.381034 -0.027339 ↓ 
CC(=O)OC[C@H](CON1Cc2c(-c3cn(C)c4ccccc34)n[nH]c2C1(C)C)OC(C)=O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.438620 0.381034 -0.057586 +0.1313 -13.13% ✅ Improved
BBBP ↑ higher 0.999970 1.000000 +0.000030 +0.0000 +0.00% ✅ Improved
CYP3A4 ↓ lower 0.046397 0.011194 -0.035203 +0.7587 -75.87% ✅ Improved
DILI ↓ lower 0.750240 0.458021 -0.292219 +0.3895 -38.95% ✅ Improved
HIA ↑ higher 0.988937 0.995235 +0.006298 +0.0064 +0.64% ✅ Improved
PGP ↓ lower 0.653441 0.630667 -0.022773 +0.0349 -3.49% ✅ Improved

Improved: 6/6 (100.0%) | Molecules: 175 | Paths: 1473

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
PGP 0.6307 ↓ 0.3 0.3307
AMES 0.3810 ↓ 0.3 0.0810
DILI 0.4580 ↓ 0.4 0.0580

✅ Passing: 3

Task Score Threshold
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0112 ↓ 0.55
HIA 0.9952 ↑ 0.2

Slide 8: Valeresol

Initial Task: HIA

SMILES: C(CCOC1=C(C=O)C(=CC=C1)O)CC(=O)O

Valeresol - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `C(CCOC1=C(C=O)C(=CC=C1)O)CC(=O)O`
**QED (Drug-likeness):** 0.5590 **Number of Blocks:** 2
▶ Step 1: HIA (+0.0107 ↑) ✅
**Before (Initial)** `CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C(=O)N[C@H](CN(C)C)C5=CC=CC=C5)C4(C)C)SC=C2`
**QED:** 0.3671 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.419049 ↓ lower
BBBP 0.778013 ↑ higher
CYP3A4 0.011948 ↓ lower
DILI 0.793920 ↓ lower
HIA 0.984575 ↑ higher
PGP 0.499705 ↓ lower
4 		**Final Optimized** `CC1(C)c2[nH]nc(N3Cc4c(C(=O)c5cccs5)n[nH]c4C3(C)C)c2CN1OCCCCC(=O)O`
**QED (Drug-likeness):** 0.2992 (-0.2597) ❌ **Number of Blocks:** 2 (+0) ➡️ **Total Block Changes:** 8
▶ Step 1: HIA (+0.0107 ↑) ✅
**Before (Initial)** `CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C(=O)N[C@H](CN(C)C)C5=CC=CC=C5)C4(C)C)SC=C2`
**QED:** 0.3671 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.419049 ↓ lower
BBBP 0.778013 ↑ higher
CYP3A4 0.011948 ↓ lower
DILI 0.793920 ↓ lower
HIA 0.984575 ↑ higher
PGP 0.499705 ↓ lower
5

Optimization Steps:

DETAILSPLACEHOLDER26

After (Step 1)

CC(=O)O[C@H](CCl)COOCCCCC(=O)O

QED: 0.2118 (-0.3472) ❌

Number of Blocks: 1 (-1) ↓

Block Changes: 3 (+1, -2)

HIA Score: 0.984511 → 0.999700 (+0.015189)

DETAILSPLACEHOLDER27

DETAILSPLACEHOLDER28

After (Step 2)

Cc1nc(-c2n[nH]c3c2CN(OCCCCC(=O)O)C3(C)C)cs1

QED: 0.7458 (+0.5340) ✅

Number of Blocks: 2 (+1) ↑

Block Changes: 3 (+2, -1)

AMES Score: 0.428290 → 0.776573 (+0.348283)

DETAILSPLACEHOLDER29

DETAILSPLACEHOLDER30

After (Step 3)

CC1(C)c2[nH]nc(N3Cc4c(C(=O)c5cccs5)n[nH]c4C3(C)C)c2CN1OCCCCC(=O)O

QED: 0.2992 (-0.4465) ❌

Number of Blocks: 2 (+0) ➡️

Block Changes: 2 (+1, -1)

PGP Score: 0.609776 → 0.498713 (-0.111063)

DETAILSPLACEHOLDER31

📊 Step Details

Step 1: HIA ✅

Original New Change
0.984511 0.999700 +0.015189 ↑ 
CC(=O)O[C@H](CCl)COOCCCCC(=O)O

Step 2: AMES ⚠️

Original New Change
0.428290 0.776573 +0.348283 ↓ 
Cc1nc(-c2n[nH]c3c2CN(OCCCCC(=O)O)C3(C)C)cs1

Step 3: PGP ✅

Original New Change
0.609776 0.498713 -0.111063 ↓ 
CC1(C)c2[nH]nc(N3Cc4c(C(=O)c5cccs5)n[nH]c4C3(C)C)c2CN1OCCCCC(=O)O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.687406 0.368299 -0.319107 +0.4642 -46.42% ✅ Improved
BBBP ↑ higher 0.001264 0.898326 +0.897062 +709.5506 +70955.06% ✅ Improved
CYP3A4 ↓ lower 0.022560 0.005592 -0.016969 +0.7521 -75.21% ✅ Improved
DILI ↓ lower 0.623776 0.676924 +0.053148 -0.0852 +8.52% ❌ Declined
HIA ↑ higher 0.984511 0.980476 -0.004035 -0.0041 -0.41% ❌ Declined
PGP ↓ lower 0.615759 0.498713 -0.117046 +0.1901 -19.01% ✅ Improved

Improved: 4/6 (66.7%) | Molecules: 85 | Paths: 1719

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
DILI 0.6769 ↓ 0.4 0.2769
PGP 0.4987 ↓ 0.3 0.1987
AMES 0.3683 ↓ 0.3 0.0683

✅ Passing: 3

Task Score Threshold
BBBP 0.8983 ↑ 0.5
CYP3A4 0.0056 ↓ 0.55
HIA 0.9805 ↑ 0.2

Slide 9: Fialuridine (FIAU)

Initial Task: DILI

SMILES: C1=C(C(=O)NC(=O)N1[C@H]2[C@H]([C@@H]([C@@H](CO)O2)O)F)I

Fialuridine (FIAU) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `C1=C(C(=O)NC(=O)N1[C@H]2[C@H]([C@@H]([C@@H](CO)O2)O)F)I`
**QED (Drug-likeness):** 0.5621 **Number of Blocks:** 1
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.717762 +0.298713 -0.7128 +71.28% ↓ lower
BBBP ❌ 0.000191 -0.777823 -0.9998 -99.98% ↑ higher
CYP3A4 ✅ 0.003685 -0.008263 +0.6916 -69.16% ↓ lower
DILI ✅ 0.691250 -0.102670 +0.1293 -12.93% ↓ lower
HIA ✅ 0.995240 +0.010665 +0.0108 +1.08% ↑ higher
PGP ❌ 0.564487 +0.064781 -0.1296 +12.96% ↓ lower
2 		**Final Optimized** `CC/C=C\CC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(OC[C@@H](CCl)OC(C)=O)C2(C)C`
**QED (Drug-likeness):** 0.1398 (-0.4222) ❌ **Number of Blocks:** 3 (+2) ↑ **Total Block Changes:** 10
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.717762 +0.298713 -0.7128 +71.28% ↓ lower
BBBP ❌ 0.000191 -0.777823 -0.9998 -99.98% ↑ higher
CYP3A4 ✅ 0.003685 -0.008263 +0.6916 -69.16% ↓ lower
DILI ✅ 0.691250 -0.102670 +0.1293 -12.93% ↓ lower
HIA ✅ 0.995240 +0.010665 +0.0108 +1.08% ↑ higher
PGP ❌ 0.564487 +0.064781 -0.1296 +12.96% ↓ lower
3

Optimization Steps:

DETAILSPLACEHOLDER34

After (Step 1)

CC(=O)O[C@H](CCl)COc1cn(C)c2ccccc12

QED: 0.6249 (+0.0629) ✅

Number of Blocks: 2 (+1) ↑

Block Changes: 3 (+2, -1)

DILI Score: 0.145744 → 0.641619 (+0.495875)

DETAILSPLACEHOLDER35

DETAILSPLACEHOLDER36

After (Step 2)

CC(=O)O[C@H](CCl)CON1Cc2c(-c3ccc(C)s3)n[nH]c2C1(C)C

QED: 0.6094 (-0.0155) ❌

Number of Blocks: 2 (+0) ➡️

Block Changes: 4 (+2, -2)

CYP3A4 Score: 0.159087 → 0.009106 (-0.149981)

DETAILSPLACEHOLDER37

DETAILSPLACEHOLDER38

After (Step 3)

CC/C=C\CC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(OC[C@@H](CCl)OC(C)=O)C2(C)C

QED: 0.1398 (-0.4696) ❌

Number of Blocks: 3 (+1) ↑

Block Changes: 3 (+2, -1)

DILI Score: 0.576163 → 0.259323 (-0.316840)

DETAILSPLACEHOLDER39

📊 Step Details

Step 1: DILI ⚠️

Original New Change
0.145744 0.641619 +0.495875 ↓ 
CC(=O)O[C@H](CCl)COc1cn(C)c2ccccc12

Step 2: CYP3A4 ✅

Original New Change
0.159087 0.009106 -0.149981 ↓ 
CC(=O)O[C@H](CCl)CON1Cc2c(-c3ccc(C)s3)n[nH]c2C1(C)C

Step 3: DILI ✅

Original New Change
0.576163 0.259323 -0.316840 ↓ 
CC/C=C\CC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(OC[C@@H](CCl)OC(C)=O)C2(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.114162 0.266793 +0.152631 -1.3370 +133.70% ❌ Declined
BBBP ↑ higher 1.000000 1.000000 +0.000000 +0.0000 +0.00% ➡️ Unchanged
CYP3A4 ↓ lower 0.000000 0.000067 +0.000067 -5806.1212 +580612.12% ❌ Declined
DILI ↓ lower 0.145744 0.259323 +0.113579 -0.7793 +77.93% ❌ Declined
HIA ↑ higher 1.000000 0.999987 -0.000013 -0.0000 -0.00% ❌ Declined
PGP ↓ lower 0.940474 0.866124 -0.074351 +0.0791 -7.91% ✅ Improved

Improved: 1/6 (16.7%) | Molecules: 271 | Paths: 19870

🔍 Safety Threshold Analysis

Status: 5/6 meet thresholds

⚠️ Below threshold: 1

Task Score Threshold Gap
PGP 0.8661 ↓ 0.3 0.5661

✅ Passing: 5

Task Score Threshold
AMES 0.2668 ↓ 0.3
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0001 ↓ 0.55
DILI 0.2593 ↓ 0.4
HIA 1.0000 ↑ 0.2

Slide 10: Ximelagatran (Exanta / oral direct thrombin inhibitor)

Initial Task: DILI

SMILES: CCOC(=O)CN[C@H](C1CCCCC1)C(=O)N2CC[C@H]2C(=O)NCC3=CC=C(C=C3)/C(=N\O)/N

Ximelagatran (Exanta / oral direct thrombin inhibitor) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CCOC(=O)CN[C@H](C1CCCCC1)C(=O)N2CC[C@H]2C(=O)NCC3=CC=C(C=C3)/C(=N\O)/N`
**QED (Drug-likeness):** 0.1308 **Number of Blocks:** 3
▶ Step 2: PGP (+0.0081 ↓) ➡️
**Before (Step 1)** `Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1`
**QED:** 0.2053 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.717762 ↓ lower
BBBP 0.000191 ↑ higher
CYP3A4 0.003685 ↓ lower
DILI 0.691250 ↓ lower
HIA 0.995240 ↑ higher
PGP 0.564487 ↓ lower
0 		**Final Optimized** `CC(=O)OC[C@H](CON1CC[C@H]1C(=O)N1Cc2c(-c3ccc([C@@H](C)C(=O)O)cc3F)n[nH]c2C1(C)C)OC(C)=O`
**QED (Drug-likeness):** 0.4148 (+0.2840) ✅ **Number of Blocks:** 3 (+0) ➡️ **Total Block Changes:** 10
▶ Step 2: PGP (+0.0081 ↓) ➡️
**Before (Step 1)** `Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1`
**QED:** 0.2053 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.717762 ↓ lower
BBBP 0.000191 ↑ higher
CYP3A4 0.003685 ↓ lower
DILI 0.691250 ↓ lower
HIA 0.995240 ↑ higher
PGP 0.564487 ↓ lower
1

Optimization Steps:

DETAILSPLACEHOLDER42

After (Step 1)

CCOC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)OC[C@@H](CCl)OC(C)=O)C1CCCCC1

QED: 0.2796 (+0.1488) ✅

Number of Blocks: 3 (+0) ➡️

Block Changes: 2 (+1, -1)

DILI Score: 0.649647 → 0.419199 (-0.230448)

DETAILSPLACEHOLDER43

DETAILSPLACEHOLDER44

After (Step 2)

CCOC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)N1Cc2c(-c3ccc(C)s3)n[nH]c2C1(C)C)C1CCCCC1

QED: 0.4934 (+0.2138) ✅

Number of Blocks: 4 (+1) ↑

Block Changes: 3 (+2, -1)

AMES Score: 0.340648 → 0.732660 (+0.392012)

DETAILSPLACEHOLDER45

DETAILSPLACEHOLDER46

After (Step 3)

CC(=O)OC[C@H](CON1CC[C@H]1C(=O)N1Cc2c(-c3ccc([C@@H](C)C(=O)O)cc3F)n[nH]c2C1(C)C)OC(C)=O

QED: 0.4148 (-0.0787) ❌

Number of Blocks: 3 (-1) ↓

Block Changes: 5 (+2, -3)

AMES Score: 0.732660 → 0.404659 (-0.328000)

DETAILSPLACEHOLDER47

📊 Step Details

Step 1: DILI ✅

Original New Change
0.649647 0.419199 -0.230448 ↓ 
CCOC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)OC[C@@H](CCl)OC(C)=O)C1CCCCC1

Step 2: AMES ⚠️

Original New Change
0.340648 0.732660 +0.392012 ↓ 
CCOC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)N1Cc2c(-c3ccc(C)s3)n[nH]c2C1(C)C)C1CCCCC1

Step 3: AMES ✅

Original New Change
0.732660 0.404659 -0.328000 ↓ 
CC(=O)OC[C@H](CON1CC[C@H]1C(=O)N1Cc2c(-c3ccc([C@@H](C)C(=O)O)cc3F)n[nH]c2C1(C)C)OC(C)=O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.720076 0.404659 -0.315416 +0.4380 -43.80% ✅ Improved
BBBP ↑ higher 0.000080 0.999947 +0.999867 +12529.0183 +1252901.83% ✅ Improved
CYP3A4 ↓ lower 0.018008 0.020061 +0.002053 -0.1140 +11.40% ❌ Declined
DILI ↓ lower 0.649647 0.408363 -0.241285 +0.3714 -37.14% ✅ Improved
HIA ↑ higher 0.997815 0.991177 -0.006638 -0.0067 -0.67% ❌ Declined
PGP ↓ lower 0.655136 0.659510 +0.004374 -0.0067 +0.67% ❌ Declined

Improved: 3/6 (50.0%) | Molecules: 283 | Paths: 3915

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
PGP 0.6595 ↓ 0.3 0.3595
AMES 0.4047 ↓ 0.3 0.1047
DILI 0.4084 ↓ 0.4 0.0084

✅ Passing: 3

Task Score Threshold
BBBP 0.9999 ↑ 0.5
CYP3A4 0.0201 ↓ 0.55
HIA 0.9912 ↑ 0.2

Slide 11: Fasiglifam (TAK-875)

Initial Task: DILI

SMILES: CC1=C(C(=CC(=C1)OCCCS(=O)(=O)C)C)C2=CC(=CC=C2)COC3=CC=C4[C@@H](CC(=O)O)COC4=C3

Fasiglifam (TAK-875) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC1=C(C(=CC(=C1)OCCCS(=O)(=O)C)C)C2=CC(=CC=C2)COC3=CC=C4[C@@H](CC(=O)O)COC4=C3`
**QED (Drug-likeness):** 0.3393 **Number of Blocks:** 4
▶ Step 2: PGP (+0.0081 ↓) ➡️
**Before (Step 1)** `Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1`
**QED:** 0.2053 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.717762 ↓ lower
BBBP 0.000191 ↑ higher
CYP3A4 0.003685 ↓ lower
DILI 0.691250 ↓ lower
HIA 0.995240 ↑ higher
PGP 0.564487 ↓ lower
8 		**Final Optimized** `Cc1cc(N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O`
**QED (Drug-likeness):** 0.0486 (-0.2907) ❌ **Number of Blocks:** 5 (+1) ↑ **Total Block Changes:** 11
▶ Step 2: PGP (+0.0081 ↓) ➡️
**Before (Step 1)** `Cc1nc(Nc2n[nH]c3c2CN(C(=O)N[C@@H](CN(C)C)Nc2nc(C)nc4ccsc24)C3(C)C)c2sccc2n1`
**QED:** 0.2053 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score Direction
AMES 0.717762 ↓ lower
BBBP 0.000191 ↑ higher
CYP3A4 0.003685 ↓ lower
DILI 0.691250 ↓ lower
HIA 0.995240 ↑ higher
PGP 0.564487 ↓ lower
9

Optimization Steps:

DETAILSPLACEHOLDER50

After (Step 1)

Cc1cc(OCCCS(C)(=O)=O)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

QED: 0.0997 (-0.2396) ❌

Number of Blocks: 3 (-1) ↓

Block Changes: 5 (+2, -3)

DILI Score: 0.605552 → 0.424327 (-0.181224)

DETAILSPLACEHOLDER51

DETAILSPLACEHOLDER52

After (Step 2)

Cc1cc(N2Cc3c(C(=O)Cc4cccs4)n[nH]c3C2(C)C)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

QED: 0.0632 (-0.0365) ❌

Number of Blocks: 4 (+1) ↑

Block Changes: 5 (+3, -2)

BBBP Score: 0.999996 → 1.000000 (+0.000004)

DETAILSPLACEHOLDER53

DETAILSPLACEHOLDER54

After (Step 3)

Cc1cc(N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

QED: 0.0486 (-0.0146) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 1 (+1, -0)

PGP Score: 0.798334 → 0.755818 (-0.042516)

DETAILSPLACEHOLDER55

📊 Step Details

Step 1: DILI ✅

Original New Change
0.605552 0.424327 -0.181224 ↓ 
Cc1cc(OCCCS(C)(=O)=O)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

Step 2: BBBP ✅

Original New Change
0.999996 1.000000 +0.000004 ↑ 
Cc1cc(N2Cc3c(C(=O)Cc4cccs4)n[nH]c3C2(C)C)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

Step 3: PGP ✅

Original New Change
0.798334 0.755818 -0.042516 ↓ 
Cc1cc(N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1C(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCOc1ccc2c(c1)OC[C@@H]2CC(=O)O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.459273 0.259236 -0.200037 +0.4356 -43.56% ✅ Improved
BBBP ↑ higher 0.999996 0.999966 -0.000030 -0.0000 -0.00% ❌ Declined
CYP3A4 ↓ lower 0.082408 0.001861 -0.080547 +0.9774 -97.74% ✅ Improved
DILI ↓ lower 0.605552 0.380775 -0.224777 +0.3712 -37.12% ✅ Improved
HIA ↑ higher 0.659498 0.996015 +0.336517 +0.5103 +51.03% ✅ Improved
PGP ↓ lower 0.636196 0.755818 +0.119622 -0.1880 +18.80% ❌ Declined

Improved: 4/6 (66.7%) | Molecules: 175 | Paths: 2055

🔍 Safety Threshold Analysis

Status: 5/6 meet thresholds

⚠️ Below threshold: 1

Task Score Threshold Gap
PGP 0.7558 ↓ 0.3 0.4558

✅ Passing: 5

Task Score Threshold
AMES 0.2592 ↓ 0.3
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0019 ↓ 0.55
DILI 0.3808 ↓ 0.4
HIA 0.9960 ↑ 0.2

Slide 12: Lapaquistat acetate (TAK-475)

Initial Task: DILI

SMILES: CC(=O)OCC(C)(C)CN1C2=CC=C(C=C2[C@@H](C3=CC=CC(=C3OC)OC)O[C@H](CC(=O)N4CCC(CC4)CC(=O)O)C1=O)Cl

Lapaquistat acetate (TAK-475) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC(=O)OCC(C)(C)CN1C2=CC=C(C=C2[C@@H](C3=CC=CC(=C3OC)OC)O[C@H](CC(=O)N4CCC(CC4)CC(=O)O)C1=O)Cl`
**QED (Drug-likeness):** 0.3403 **Number of Blocks:** 3
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.713346 +0.294297 -0.7023 +70.23% ↓ lower
BBBP ❌ 0.000145 -0.777868 -0.9998 -99.98% ↑ higher
CYP3A4 ✅ 0.004173 -0.007774 +0.6507 -65.07% ↓ lower
DILI ✅ 0.638678 -0.155242 +0.1955 -19.55% ↓ lower
HIA ✅ 0.995237 +0.010662 +0.0108 +1.08% ↑ higher
PGP ❌ 0.572543 +0.072838 -0.1458 +14.58% ↓ lower
6 		**Final Optimized** `CC(C)CC(=O)c1n[nH]c2c1CN(c1n[nH]c3c1CN(c1n[nH]c4c1CN(NCc1ccc(/C(N)=N\O)cc1)C4(C)C)C3(C)C)C2(C)C`
**QED (Drug-likeness):** 0.0496 (-0.2907) ❌ **Number of Blocks:** 4 (+1) ↑ **Total Block Changes:** 13
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.713346 +0.294297 -0.7023 +70.23% ↓ lower
BBBP ❌ 0.000145 -0.777868 -0.9998 -99.98% ↑ higher
CYP3A4 ✅ 0.004173 -0.007774 +0.6507 -65.07% ↓ lower
DILI ✅ 0.638678 -0.155242 +0.1955 -19.55% ↓ lower
HIA ✅ 0.995237 +0.010662 +0.0108 +1.08% ↑ higher
PGP ❌ 0.572543 +0.072838 -0.1458 +14.58% ↓ lower
7

Optimization Steps:

DETAILSPLACEHOLDER58

After (Step 1)

CC(=O)OCC(C)(C)CN1C(=O)[C@@H](CC(=O)NCc2ccc(/C(N)=N\O)cc2)O[C@@H](N2Cc3c(OCC(C)C)n[nH]c3C2(C)C)c2cc(Cl)ccc21

QED: 0.0614 (-0.2789) ❌

Number of Blocks: 2 (-1) ↓

Block Changes: 5 (+2, -3)

DILI Score: 0.602326 → 0.416277 (-0.186049)

DETAILSPLACEHOLDER59

DETAILSPLACEHOLDER60

After (Step 2)

CC(=O)OC[C@H](COc1n[nH]c2c1CN(c1n[nH]c3c1CN(NCc1ccc(/C(N)=N\O)cc1)C3(C)C)C2(C)C)OC(C)=O

QED: 0.0699 (+0.0085) ✅

Number of Blocks: 4 (+2) ↑

Block Changes: 6 (+4, -2)

CYP3A4 Score: 0.050735 → 0.020237 (-0.030498)

DETAILSPLACEHOLDER61

DETAILSPLACEHOLDER62

After (Step 3)

CC(C)CC(=O)c1n[nH]c2c1CN(c1n[nH]c3c1CN(c1n[nH]c4c1CN(NCc1ccc(/C(N)=N\O)cc1)C4(C)C)C3(C)C)C2(C)C

QED: 0.0496 (-0.0203) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 2 (+1, -1)

CYP3A4 Score: 0.020237 → 0.001016 (-0.019221)

DETAILSPLACEHOLDER63

📊 Step Details

Step 1: DILI ✅

Original New Change
0.602326 0.416277 -0.186049 ↓ 
CC(=O)OCC(C)(C)CN1C(=O)[C@@H](CC(=O)NCc2ccc(/C(N)=N\O)cc2)O[C@@H](N2Cc3c(OCC(C)C)n[nH]c3C2(C)C)c2cc(Cl)ccc21

Step 2: CYP3A4 ✅

Original New Change
0.050735 0.020237 -0.030498 ↓ 
CC(=O)OC[C@H](COc1n[nH]c2c1CN(c1n[nH]c3c1CN(NCc1ccc(/C(N)=N\O)cc1)C3(C)C)C2(C)C)OC(C)=O

Step 3: CYP3A4 ✅

Original New Change
0.020237 0.001016 -0.019221 ↓ 
CC(C)CC(=O)c1n[nH]c2c1CN(c1n[nH]c3c1CN(c1n[nH]c4c1CN(NCc1ccc(/C(N)=N\O)cc1)C4(C)C)C3(C)C)C2(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.419620 0.683061 +0.263441 -0.6278 +62.78% ❌ Declined
BBBP ↑ higher 0.999985 0.000186 -0.999799 -0.9998 -99.98% ❌ Declined
CYP3A4 ↓ lower 0.035988 0.001016 -0.034972 +0.9718 -97.18% ✅ Improved
DILI ↓ lower 0.602326 0.619393 +0.017067 -0.0283 +2.83% ❌ Declined
HIA ↑ higher 0.980337 0.987780 +0.007443 +0.0076 +0.76% ✅ Improved
PGP ↓ lower 0.662407 0.592538 -0.069869 +0.1055 -10.55% ✅ Improved

Improved: 3/6 (50.0%) | Molecules: 415 | Paths: 7886

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0002 ↑ 0.5 0.4998
AMES 0.6831 ↓ 0.3 0.3831
PGP 0.5925 ↓ 0.3 0.2925
DILI 0.6194 ↓ 0.4 0.2194

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0010 ↓ 0.55
HIA 0.9878 ↑ 0.2

Slide 13: Danuglipron (Pfizer)

Initial Task: DILI

SMILES: C1=CC(=NC(=C1)OCC2=CC=C(C=C2F)C#N)C3CCN(CC3)CC4=NC5=CC=C(C=C5N4C[C@@H]6CCO6)C(=O)O

Danuglipron (Pfizer) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `C1=CC(=NC(=C1)OCC2=CC=C(C=C2F)C#N)C3CCN(CC3)CC4=NC5=CC=C(C=C5N4C[C@@H]6CCO6)C(=O)O`
**QED (Drug-likeness):** 0.3107 **Number of Blocks:** 4
▶ Step 3: CYP3A4 (-0.0033 ↓) ✅
**Before (Step 2)** `Cc1nc(N[C@H](CN(C)C)NC(=O)N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)c2sccc2n1`
**QED:** 0.1259 **Number of Blocks:** 5
▶ All ADMET Scores
Task Score Direction
AMES 0.713346 ↓ lower
BBBP 0.000145 ↑ higher
CYP3A4 0.004173 ↓ lower
DILI 0.638678 ↓ lower
HIA 0.995237 ↑ higher
PGP 0.572543 ↓ lower
4 		**Final Optimized** `Cc1cc(N2Cc3c(N4Cc5c(-c6c(C)cc(NC78CC9CC(CC(C9)C7)C8)cc6C)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1-c1cccc(OCc2ccc(C#N)cc2F)n1`
**QED (Drug-likeness):** 0.1314 (-0.1793) ❌ **Number of Blocks:** 7 (+3) ↑ **Total Block Changes:** 16
▶ Step 3: CYP3A4 (-0.0033 ↓) ✅
**Before (Step 2)** `Cc1nc(N[C@H](CN(C)C)NC(=O)N2Cc3c(N4Cc5c(C(=O)Cc6cccs6)n[nH]c5C4(C)C)n[nH]c3C2(C)C)c2sccc2n1`
**QED:** 0.1259 **Number of Blocks:** 5
▶ All ADMET Scores
Task Score Direction
AMES 0.713346 ↓ lower
BBBP 0.000145 ↑ higher
CYP3A4 0.004173 ↓ lower
DILI 0.638678 ↓ lower
HIA 0.995237 ↑ higher
PGP 0.572543 ↓ lower
5

Optimization Steps:

DETAILSPLACEHOLDER66

After (Step 1)

COc1ccc(-c2n[nH]c3c2CN(CN2CCC(c4cccc(OCc5ccc(C#N)cc5F)n4)CC2)C3(C)C)cc1O

QED: 0.2738 (-0.0369) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 6 (+3, -3)

DILI Score: 0.804817 → 0.721803 (-0.083013)

DETAILSPLACEHOLDER67

DETAILSPLACEHOLDER68

After (Step 2)

CC1(C)c2[nH]nc(N3Cc4c(NC56CC7CC(CC(C7)C5)C6)n[nH]c4C3(C)C)c2CN1CN1CCC(c2cccc(OCc3ccc(C#N)cc3F)n2)CC1

QED: 0.1586 (-0.1151) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 7 (+4, -3)

PGP Score: 0.598865 → 0.554803 (-0.044061)

DETAILSPLACEHOLDER69

DETAILSPLACEHOLDER70

After (Step 3)

Cc1cc(N2Cc3c(N4Cc5c(-c6c(C)cc(NC78CC9CC(CC(C9)C7)C8)cc6C)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1-c1cccc(OCc2ccc(C#N)cc2F)n1

QED: 0.1314 (-0.0272) ❌

Number of Blocks: 7 (+2) ↑

Block Changes: 3 (+2, -1)

PGP Score: 0.554803 → 0.571472 (+0.016669)

DETAILSPLACEHOLDER71

📊 Step Details

Step 1: DILI ✅

Original New Change
0.804817 0.721803 -0.083013 ↓ 
COc1ccc(-c2n[nH]c3c2CN(CN2CCC(c4cccc(OCc5ccc(C#N)cc5F)n4)CC2)C3(C)C)cc1O

Step 2: PGP ✅

Original New Change
0.598865 0.554803 -0.044061 ↓ 
CC1(C)c2[nH]nc(N3Cc4c(NC56CC7CC(CC(C7)C5)C6)n[nH]c4C3(C)C)c2CN1CN1CCC(c2cccc(OCc3ccc(C#N)cc3F)n2)CC1

Step 3: PGP ⚠️

Original New Change
0.554803 0.571472 +0.016669 ↓ 
Cc1cc(N2Cc3c(N4Cc5c(-c6c(C)cc(NC78CC9CC(CC(C9)C7)C8)cc6C)n[nH]c5C4(C)C)n[nH]c3C2(C)C)cc(C)c1-c1cccc(OCc2ccc(C#N)cc2F)n1

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.755845 0.648178 -0.107668 +0.1424 -14.24% ✅ Improved
BBBP ↑ higher 0.000238 0.000290 +0.000053 +0.2221 +22.21% ✅ Improved
CYP3A4 ↓ lower 0.009860 0.001107 -0.008752 +0.8877 -88.77% ✅ Improved
DILI ↓ lower 0.804817 0.550500 -0.254317 +0.3160 -31.60% ✅ Improved
HIA ↑ higher 0.993762 0.966419 -0.027343 -0.0275 -2.75% ❌ Declined
PGP ↓ lower 0.573991 0.571472 -0.002519 +0.0044 -0.44% ✅ Improved

Improved: 5/6 (83.3%) | Molecules: 385 | Paths: 5311

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0003 ↑ 0.5 0.4997
AMES 0.6482 ↓ 0.3 0.3482
PGP 0.5715 ↓ 0.3 0.2715
DILI 0.5505 ↓ 0.4 0.1505

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0011 ↓ 0.55
HIA 0.9664 ↑ 0.2

Slide 14: Rosiglitazone

Initial Task: BBBP

SMILES: CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC=CC=N3

Rosiglitazone - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC=CC=N3`
**QED (Drug-likeness):** 0.8209 **Number of Blocks:** 4
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86% ↓ lower
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97% ↑ higher
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56% ↓ lower
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98% ↓ lower
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35% ↑ higher
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44% ↓ lower
2 		**Final Optimized** `CCCCCCC(CCCC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C`
**QED (Drug-likeness):** 0.0186 (-0.8023) ❌ **Number of Blocks:** 6 (+2) ↑ **Total Block Changes:** 15
▶ All ADMET Scores
Task Score vs Initial Rel. Improvement % Change Direction
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86% ↓ lower
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97% ↑ higher
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56% ↓ lower
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98% ↓ lower
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35% ↑ higher
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44% ↓ lower
3

Optimization Steps:

DETAILSPLACEHOLDER74

After (Step 1)

CCCCC(CC)COc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

QED: 0.1564 (-0.6645) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 8 (+4, -4)

BBBP Score: 0.646056 → 0.000386 (-0.645670)

DETAILSPLACEHOLDER75

DETAILSPLACEHOLDER76

After (Step 2)

CCCCC(CC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

QED: 0.0569 (-0.0995) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 5 (+3, -2)

AMES Score: 0.587563 → 0.499352 (-0.088211)

DETAILSPLACEHOLDER77

DETAILSPLACEHOLDER78

After (Step 3)

CCCCCCC(CCCC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

QED: 0.0186 (-0.0383) ❌

Number of Blocks: 6 (+1) ↑

Block Changes: 2 (+1, -1)

CYP3A4 Score: 0.000004 → 0.000001 (-0.000004)

DETAILSPLACEHOLDER79

📊 Step Details

Step 1: BBBP ⚠️

Original New Change
0.646056 0.000386 -0.645670 ↑ 
CCCCC(CC)COc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

Step 2: AMES ✅

Original New Change
0.587563 0.499352 -0.088211 ↓ 
CCCCC(CC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

Step 3: CYP3A4 ✅

Original New Change
0.000004 0.000001 -0.000004 ↓ 
CCCCCCC(CCCC)COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)Nc1n[nH]c2c1CN(N(C)CCOC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)NCC1SC(=O)NC1=O)C2(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.408545 0.155246 -0.253299 +0.6200 -62.00% ✅ Improved
BBBP ↑ higher 0.646056 1.000000 +0.353944 +0.5479 +54.79% ✅ Improved
CYP3A4 ↓ lower 0.080225 0.000001 -0.080224 +1.0000 -100.00% ✅ Improved
DILI ↓ lower 0.804278 0.306504 -0.497774 +0.6189 -61.89% ✅ Improved
HIA ↑ higher 0.998374 1.000000 +0.001626 +0.0016 +0.16% ✅ Improved
PGP ↓ lower 0.538867 0.882034 +0.343167 -0.6368 +63.68% ❌ Declined

Improved: 5/6 (83.3%) | Molecules: 373 | Paths: 7117

🔍 Safety Threshold Analysis

Status: 5/6 meet thresholds

⚠️ Below threshold: 1

Task Score Threshold Gap
PGP 0.8820 ↓ 0.3 0.5820

✅ Passing: 5

Task Score Threshold
AMES 0.1552 ↓ 0.3
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0000 ↓ 0.55
DILI 0.3065 ↓ 0.4
HIA 1.0000 ↑ 0.2

Slide 15: Paclitaxel / other taxanes

Initial Task: BBBP

SMILES: CC1=C2[C@H](C(=O)[C@]3(C)[C@H](C[C@@H]4[C@@](CO4)([C@@]3(C)[C@@H]([C@](C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)(C2(C)C)O)OC(=O)C7=CC=CC=C7)OC(=O)C)O)OC(=O)C

Paclitaxel / other taxanes - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC1=C2[C@H](C(=O)[C@]3(C)[C@H](C[C@@H]4[C@@](CO4)([C@@]3(C)[C@@H]([C@](C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)(C2(C)C)O)OC(=O)C7=CC=CC=C7)OC(=O)C)O)OC(=O)C`
**QED (Drug-likeness):** 0.1280 **Number of Blocks:** 4
▶ Show ADMET Scores
Task Score
AMES 0.721609
BBBP 0.000066
CYP3A4 0.009376
DILI 0.714050
HIA 0.989571
PGP 0.702944
0 		**Final Optimized** `CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)N1Cc2c(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)OC[C@@H](CCl)OC(C)=O)n[nH]c2C1(C)C`
**QED (Drug-likeness):** 0.0507 (-0.0773) ❌ **Number of Blocks:** 5 (+1) ↑ **Total Block Changes:** 18
▶ Show ADMET Scores
Task Score
AMES 0.721609
BBBP 0.000066
CYP3A4 0.009376
DILI 0.714050
HIA 0.989571
PGP 0.702944
1

Optimization Steps:

DETAILSPLACEHOLDER82

After (Step 1)

CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](ON[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)c3ccoc3C)[C@]3(C)[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C

QED: 0.0210 (-0.1070) ❌

Number of Blocks: 4 (+0) ➡️

Block Changes: 7 (+4, -3)

BBBP Score: 0.000153 → 0.000113 (-0.000040)

DETAILSPLACEHOLDER83

DETAILSPLACEHOLDER84

After (Step 2)

CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)N1Cc2c(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)CC3SC(=O)NC3=O)n[nH]c2C1(C)C

QED: 0.0672 (+0.0462) ✅

Number of Blocks: 5 (+1) ↑

Block Changes: 3 (+2, -1)

AMES Score: 0.677737 → 0.576776 (-0.100962)

DETAILSPLACEHOLDER85

DETAILSPLACEHOLDER86

After (Step 3)

CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)N1Cc2c(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)OC[C@@H](CCl)OC(C)=O)n[nH]c2C1(C)C

QED: 0.0507 (-0.0165) ❌

Number of Blocks: 5 (+0) ➡️

Block Changes: 8 (+4, -4)

AMES Score: 0.576776 → 0.233688 (-0.343087)

DETAILSPLACEHOLDER87

📊 Step Details

Step 1: BBBP ⚠️

Original New Change
0.000153 0.000113 -0.000040 ↑ 
CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](ON[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)c3ccoc3C)[C@]3(C)[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C

Step 2: AMES ✅

Original New Change
0.677737 0.576776 -0.100962 ↓ 
CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)N1Cc2c(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)CC3SC(=O)NC3=O)n[nH]c2C1(C)C

Step 3: AMES ✅

Original New Change
0.576776 0.233688 -0.343087 ↓ 
CC(=O)O[C@H](CCl)CON[C@@H](c1ccccc1)[C@@H](O)C(=O)N1Cc2c(N[C@H](Cc3cc(Br)c(O)c(Br)c3)C(=O)OC[C@@H](CCl)OC(C)=O)n[nH]c2C1(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.766300 0.233688 -0.532611 +0.6950 -69.50% ✅ Improved
BBBP ↑ higher 0.000153 1.000000 +0.999847 +6552.6969 +655269.69% ✅ Improved
CYP3A4 ↓ lower 0.009794 0.001079 -0.008715 +0.8899 -88.99% ✅ Improved
DILI ↓ lower 0.767576 0.459665 -0.307911 +0.4011 -40.11% ✅ Improved
HIA ↑ higher 0.750817 0.999811 +0.248993 +0.3316 +33.16% ✅ Improved
PGP ↓ lower 0.573305 0.862906 +0.289601 -0.5051 +50.51% ❌ Declined

Improved: 5/6 (83.3%) | Molecules: 187 | Paths: 2468

🔍 Safety Threshold Analysis

Status: 4/6 meet thresholds

⚠️ Below threshold: 2

Task Score Threshold Gap
PGP 0.8629 ↓ 0.3 0.5629
DILI 0.4597 ↓ 0.4 0.0597

✅ Passing: 4

Task Score Threshold
AMES 0.2337 ↓ 0.3
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0011 ↓ 0.55
HIA 0.9998 ↑ 0.2

Slide 16: Mibefradil (Posicor)

Initial Task: CYP3A4

SMILES: CC(C)[C@H]1C2=CC=C(C=C2CC[C@@]1(CCN(C)CCCC3=NC4=C(C=CC=C4)N3)OC(=O)COC)F

Mibefradil (Posicor) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC(C)[C@H]1C2=CC=C(C=C2CC[C@@]1(CCN(C)CCCC3=NC4=C(C=CC=C4)N3)OC(=O)COC)F`
**QED (Drug-likeness):** 0.3672 **Number of Blocks:** 3
▶ Show ADMET Scores
Task Score
AMES 0.721609
BBBP 0.000066
CYP3A4 0.009376
DILI 0.714050
HIA 0.989571
PGP 0.702944
8 		**Final Optimized** `Cc1ccc(C(=O)[C@@H](Cc2cc(Br)c(O)c(Br)c2)Nc2n[nH]c3c2CN(c2n[nH]c4c2CN(c2ccc(C#N)cc2F)C4(C)C)C3(C)C)s1`
**QED (Drug-likeness):** 0.1154 (-0.2518) ❌ **Number of Blocks:** 5 (+2) ↑ **Total Block Changes:** 11
▶ Show ADMET Scores
Task Score
AMES 0.721609
BBBP 0.000066
CYP3A4 0.009376
DILI 0.714050
HIA 0.989571
PGP 0.702944
9

Optimization Steps:

DETAILSPLACEHOLDER90

After (Step 1)

Cc1nc(Nc2n[nH]c3c2CN(CCCN(C)CC[C@@]2(Oc4ccc(C#N)cc4F)CCc4cc(F)ccc4[C@@H]2C(C)C)C3(C)C)c2sccc2n1

QED: 0.1319 (-0.2353) ❌

Number of Blocks: 3 (+0) ➡️

Block Changes: 6 (+3, -3)

CYP3A4 Score: 0.020786 → 0.012962 (-0.007824)

DETAILSPLACEHOLDER91

DETAILSPLACEHOLDER92

After (Step 2)

Cc1nc(Nc2n[nH]c3c2CN(c2n[nH]c4c2CN(c2ccc(C#N)cc2F)C4(C)C)C3(C)C)c2sccc2n1

QED: 0.2579 (+0.1260) ✅

Number of Blocks: 4 (+1) ↑

Block Changes: 2 (+1, -1)

AMES Score: 0.735399 → 0.746586 (+0.011187)

DETAILSPLACEHOLDER93

DETAILSPLACEHOLDER94

After (Step 3)

Cc1ccc(C(=O)[C@@H](Cc2cc(Br)c(O)c(Br)c2)Nc2n[nH]c3c2CN(c2n[nH]c4c2CN(c2ccc(C#N)cc2F)C4(C)C)C3(C)C)s1

QED: 0.1154 (-0.1425) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 3 (+2, -1)

CYP3A4 Score: 0.000895 → 0.000141 (-0.000755)

DETAILSPLACEHOLDER95

📊 Step Details

Step 1: CYP3A4 ✅

Original New Change
0.020786 0.012962 -0.007824 ↓ 
Cc1nc(Nc2n[nH]c3c2CN(CCCN(C)CC[C@@]2(Oc4ccc(C#N)cc4F)CCc4cc(F)ccc4[C@@H]2C(C)C)C3(C)C)c2sccc2n1

Step 2: AMES ⚠️

Original New Change
0.735399 0.746586 +0.011187 ↓ 
Cc1nc(Nc2n[nH]c3c2CN(c2n[nH]c4c2CN(c2ccc(C#N)cc2F)C4(C)C)C3(C)C)c2sccc2n1

Step 3: CYP3A4 ✅

Original New Change
0.000895 0.000141 -0.000755 ↓ 
Cc1ccc(C(=O)[C@@H](Cc2cc(Br)c(O)c(Br)c2)Nc2n[nH]c3c2CN(c2n[nH]c4c2CN(c2ccc(C#N)cc2F)C4(C)C)C3(C)C)s1

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.456651 0.665578 +0.208928 -0.4575 +45.75% ❌ Declined
BBBP ↑ higher 0.999996 0.000031 -0.999965 -1.0000 -100.00% ❌ Declined
CYP3A4 ↓ lower 0.020786 0.000141 -0.020645 +0.9932 -99.32% ✅ Improved
DILI ↓ lower 0.675483 0.393913 -0.281570 +0.4168 -41.68% ✅ Improved
HIA ↑ higher 0.994189 0.999665 +0.005475 +0.0055 +0.55% ✅ Improved
PGP ↓ lower 0.700888 0.747508 +0.046620 -0.0665 +6.65% ❌ Declined

Improved: 3/6 (50.0%) | Molecules: 283 | Paths: 5578

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
BBBP 0.0000 ↑ 0.5 0.5000
PGP 0.7475 ↓ 0.3 0.4475
AMES 0.6656 ↓ 0.3 0.3656

✅ Passing: 3

Task Score Threshold
CYP3A4 0.0001 ↓ 0.55
DILI 0.3939 ↓ 0.4
HIA 0.9997 ↑ 0.2

Slide 17: Nefazodone (Serzone)

Initial Task: CYP3A4

SMILES: CCC1=NN(CCCN2CCN(CC2)C3=CC=CC(=C3)Cl)C(=O)N1CCOC4=CC=CC=C4

Nefazodone (Serzone) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CCC1=NN(CCCN2CCN(CC2)C3=CC=CC(=C3)Cl)C(=O)N1CCOC4=CC=CC=C4`
**QED (Drug-likeness):** 0.4542 **Number of Blocks:** 2
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ✅ 0.528857 -0.192753 +0.2671 -26.71%
BBBP ✅ 0.000205 +0.000139 +2.1037 +210.37%
CYP3A4 ✅ 0.000009 -0.009367 +0.9991 -99.91%
DILI ✅ 0.525996 -0.188054 +0.2634 -26.34%
HIA ✅ 0.999984 +0.010413 +0.0105 +1.05%
PGP ❌ 0.824368 +0.121425 -0.1727 +17.27%
6 		**Final Optimized** `CC1(C)c2[nH]nc(C(=O)c3ccc(Br)o3)c2CN1OCCCS(C)(=O)=O`
**QED (Drug-likeness):** 0.5145 (+0.0603) ✅ **Number of Blocks:** 1 (-1) ↓ **Total Block Changes:** 9
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ✅ 0.528857 -0.192753 +0.2671 -26.71%
BBBP ✅ 0.000205 +0.000139 +2.1037 +210.37%
CYP3A4 ✅ 0.000009 -0.009367 +0.9991 -99.91%
DILI ✅ 0.525996 -0.188054 +0.2634 -26.34%
HIA ✅ 0.999984 +0.010413 +0.0105 +1.05%
PGP ❌ 0.824368 +0.121425 -0.1727 +17.27%
7

Optimization Steps:

DETAILSPLACEHOLDER98

After (Step 1)

CS(=O)(=O)CCCOCC1SC(=O)NC1=O

QED: 0.6697 (+0.2155) ✅

Number of Blocks: 1 (-1) ↓

Block Changes: 3 (+1, -2)

CYP3A4 Score: 0.024539 → 0.001181 (-0.023358)

DETAILSPLACEHOLDER99

DETAILSPLACEHOLDER100

After (Step 2)

CS(=O)(=O)CCCONCc1ccc(/C(N)=N\O)cc1

QED: 0.2082 (-0.4615) ❌

Number of Blocks: 2 (+1) ↑

Block Changes: 3 (+2, -1)

AMES Score: 0.243126 → 0.686480 (+0.443354)

DETAILSPLACEHOLDER101

DETAILSPLACEHOLDER102

After (Step 3)

CC1(C)c2[nH]nc(C(=O)c3ccc(Br)o3)c2CN1OCCCS(C)(=O)=O

QED: 0.5145 (+0.3062) ✅

Number of Blocks: 1 (-1) ↓

Block Changes: 3 (+1, -2)

PGP Score: 0.675115 → 0.841080 (+0.165965)

DETAILSPLACEHOLDER103

📊 Step Details

Step 1: CYP3A4 ✅

Original New Change
0.024539 0.001181 -0.023358 ↓ 
CS(=O)(=O)CCCOCC1SC(=O)NC1=O

Step 2: AMES ⚠️

Original New Change
0.243126 0.686480 +0.443354 ↓ 
CS(=O)(=O)CCCONCc1ccc(/C(N)=N\O)cc1

Step 3: PGP ⚠️

Original New Change
0.675115 0.841080 +0.165965 ↓ 
CC1(C)c2[nH]nc(C(=O)c3ccc(Br)o3)c2CN1OCCCS(C)(=O)=O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.373806 0.284693 -0.089113 +0.2384 -23.84% ✅ Improved
BBBP ↑ higher 0.988244 1.000000 +0.011756 +0.0119 +1.19% ✅ Improved
CYP3A4 ↓ lower 0.024539 0.000204 -0.024335 +0.9917 -99.17% ✅ Improved
DILI ↓ lower 0.803705 0.390386 -0.413319 +0.5143 -51.43% ✅ Improved
HIA ↑ higher 0.999946 0.999757 -0.000189 -0.0002 -0.02% ❌ Declined
PGP ↓ lower 0.605185 0.841080 +0.235895 -0.3898 +38.98% ❌ Declined

Improved: 4/6 (66.7%) | Molecules: 301 | Paths: 7666

🔍 Safety Threshold Analysis

Status: 5/6 meet thresholds

⚠️ Below threshold: 1

Task Score Threshold Gap
PGP 0.8411 ↓ 0.3 0.5411

✅ Passing: 5

Task Score Threshold
AMES 0.2847 ↓ 0.3
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0002 ↓ 0.55
DILI 0.3904 ↓ 0.4
HIA 0.9998 ↑ 0.2

Slide 18: GSK1059615

Initial Task: HIA

SMILES: O=C(N/C1=C/C2=CC=C3N=CC=C(C4=CC=NC=C4)C3=C2)SC1=O

GSK1059615 - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `O=C(N/C1=C/C2=CC=C3N=CC=C(C4=CC=NC=C4)C3=C2)SC1=O`
**QED (Drug-likeness):** 0.7253 **Number of Blocks:** 3
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
04 		**Final Optimized** `CC1(C)c2[nH]nc(C(=O)Cc3cccs3)c2CN1c1n[nH]c2c1CN(c1ccnc3ccc(C=C4NC(=O)SC4=O)cc13)C2(C)C`
**QED (Drug-likeness):** 0.1491 (-0.5762) ❌ **Number of Blocks:** 5 (+2) ↑ **Total Block Changes:** 6
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
05

Optimization Steps:

DETAILSPLACEHOLDER106

After (Step 1)

O=C1NC(=Cc2ccc3nccc(C=C4NC(=O)SC4=O)c3c2)C(=O)S1

QED: 0.7683 (+0.0430) ✅

Number of Blocks: 3 (+0) ➡️

Block Changes: 3 (+1, -2)

HIA Score: 0.885416 → 0.992403 (+0.106986)

DETAILSPLACEHOLDER107

DETAILSPLACEHOLDER108

After (Step 2)

CC1(C)c2[nH]nc(C(=O)Cc3cccs3)c2CN1c1ccnc2ccc(C=C3NC(=O)SC3=O)cc12

QED: 0.2837 (-0.4847) ❌

Number of Blocks: 4 (+1) ↑

Block Changes: 2 (+2, -0)

PGP Score: 0.675779 → 0.597692 (-0.078087)

DETAILSPLACEHOLDER109

DETAILSPLACEHOLDER110

After (Step 3)

CC1(C)c2[nH]nc(C(=O)Cc3cccs3)c2CN1c1n[nH]c2c1CN(c1ccnc3ccc(C=C4NC(=O)SC4=O)cc13)C2(C)C

QED: 0.1491 (-0.1346) ❌

Number of Blocks: 5 (+1) ↑

Block Changes: 1 (+1, -0)

PGP Score: 0.597692 → 0.561292 (-0.036400)

DETAILSPLACEHOLDER111

📊 Step Details

Step 1: HIA ✅

Original New Change
0.885416 0.992403 +0.106986 ↑ 
O=C1NC(=Cc2ccc3nccc(C=C4NC(=O)SC4=O)c3c2)C(=O)S1

Step 2: PGP ✅

Original New Change
0.675779 0.597692 -0.078087 ↓ 
CC1(C)c2[nH]nc(C(=O)Cc3cccs3)c2CN1c1ccnc2ccc(C=C3NC(=O)SC3=O)cc12

Step 3: PGP ✅

Original New Change
0.597692 0.561292 -0.036400 ↓ 
CC1(C)c2[nH]nc(C(=O)Cc3cccs3)c2CN1c1n[nH]c2c1CN(c1ccnc3ccc(C=C4NC(=O)SC4=O)cc13)C2(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.729690 0.701288 -0.028402 +0.0389 -3.89% ✅ Improved
BBBP ↑ higher 0.001116 0.000159 -0.000957 -0.8576 -85.76% ❌ Declined
CYP3A4 ↓ lower 0.017947 0.003058 -0.014888 +0.8296 -82.96% ✅ Improved
DILI ↓ lower 0.885647 0.648698 -0.236948 +0.2675 -26.75% ✅ Improved
HIA ↑ higher 0.885416 0.974224 +0.088808 +0.1003 +10.03% ✅ Improved
PGP ↓ lower 0.542834 0.561292 +0.018458 -0.0340 +3.40% ❌ Declined

Improved: 4/6 (66.7%) | Molecules: 67 | Paths: 88

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0002 ↑ 0.5 0.4998
AMES 0.7013 ↓ 0.3 0.4013
PGP 0.5613 ↓ 0.3 0.2613
DILI 0.6487 ↓ 0.4 0.2487

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0031 ↓ 0.55
HIA 0.9742 ↑ 0.2

Slide 19: Neflamapimod (VX-745)

Initial Task: HIA

SMILES: O=c1ncn2nc(Sc3ccccc3)ccc2c1-c1c(Cl)cccc1Cl

Neflamapimod (VX-745) - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `O=c1ncn2nc(Sc3ccccc3)ccc2c1-c1c(Cl)cccc1Cl`
**QED (Drug-likeness):** 0.4735 **Number of Blocks:** 2
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
12 		**Final Optimized** `CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O`
**QED (Drug-likeness):** 0.3409 (-0.1326) ❌ **Number of Blocks:** 4 (+2) ↑ **Total Block Changes:** 10
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
13

Optimization Steps:

DETAILSPLACEHOLDER114

After (Step 1)

O=C1NC(=CCC2SC(=O)NC2=O)C(=O)S1

QED: 0.7044 (+0.2309) ✅

Number of Blocks: 2 (+0) ➡️

Block Changes: 4 (+2, -2)

HIA Score: 0.988214 → 1.000000 (+0.011786)

DETAILSPLACEHOLDER115

DETAILSPLACEHOLDER116

After (Step 2)

CC(C)COc1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

QED: 0.8206 (+0.1163) ✅

Number of Blocks: 2 (+0) ➡️

Block Changes: 2 (+1, -1)

PGP Score: 0.675575 → 0.621777 (-0.053797)

DETAILSPLACEHOLDER117

DETAILSPLACEHOLDER118

After (Step 3)

CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O

QED: 0.3409 (-0.4797) ❌

Number of Blocks: 4 (+2) ↑

Block Changes: 4 (+3, -1)

PGP Score: 0.621777 → 0.627767 (+0.005990)

DETAILSPLACEHOLDER119

📊 Step Details

Step 1: HIA ✅

Original New Change
0.988214 1.000000 +0.011786 ↑ 
O=C1NC(=CCC2SC(=O)NC2=O)C(=O)S1

Step 2: PGP ✅

Original New Change
0.675575 0.621777 -0.053797 ↓ 
CC(C)COc1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

Step 3: PGP ⚠️

Original New Change
0.621777 0.627767 +0.005990 ↓ 
CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.675174 0.314901 -0.360274 +0.5336 -53.36% ✅ Improved
BBBP ↑ higher 0.000046 0.999992 +0.999947 +21894.4005 +2189440.05% ✅ Improved
CYP3A4 ↓ lower 0.002328 0.006490 +0.004162 -1.7876 +178.76% ❌ Declined
DILI ↓ lower 0.771123 0.495032 -0.276091 +0.3580 -35.80% ✅ Improved
HIA ↑ higher 0.988214 0.999245 +0.011031 +0.0112 +1.12% ✅ Improved
PGP ↓ lower 0.672094 0.627767 -0.044327 +0.0660 -6.60% ✅ Improved

Improved: 5/6 (83.3%) | Molecules: 49 | Paths: 127

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
PGP 0.6278 ↓ 0.3 0.3278
DILI 0.4950 ↓ 0.4 0.0950
AMES 0.3149 ↓ 0.3 0.0149

✅ Passing: 3

Task Score Threshold
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0065 ↓ 0.55
HIA 0.9992 ↑ 0.2

Slide 20: SAR260301

Initial Task: CYP3A4

SMILES: O=C1N=C(CC(N2[C@@H](C)CC3=C2C=CC=C3)=O)NC(N4CCOCC4)=C1

SAR260301 - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `O=C1N=C(CC(N2[C@@H](C)CC3=C2C=CC=C3)=O)NC(N4CCOCC4)=C1`
**QED (Drug-likeness):** 0.8939 **Number of Blocks:** 2
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
20 		**Final Optimized** `CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O`
**QED (Drug-likeness):** 0.3409 (-0.5530) ❌ **Number of Blocks:** 4 (+2) ↑ **Total Block Changes:** 8
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
21

Optimization Steps:

DETAILSPLACEHOLDER122

After (Step 1)

O=C1NC(=Cc2nc(=O)cc(N3CCOCC3)[nH]2)C(=O)S1

QED: 0.7369 (-0.1570) ❌

Number of Blocks: 2 (+0) ➡️

Block Changes: 2 (+1, -1)

CYP3A4 Score: 0.038089 → 0.034567 (-0.003522)

DETAILSPLACEHOLDER123

DETAILSPLACEHOLDER124

After (Step 2)

CC(C)COc1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

QED: 0.8206 (+0.0838) ✅

Number of Blocks: 2 (+0) ➡️

Block Changes: 2 (+1, -1)

PGP Score: 0.755234 → 0.621777 (-0.133457)

DETAILSPLACEHOLDER125

DETAILSPLACEHOLDER126

After (Step 3)

CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O

QED: 0.3409 (-0.4797) ❌

Number of Blocks: 4 (+2) ↑

Block Changes: 4 (+3, -1)

PGP Score: 0.621777 → 0.627767 (+0.005990)

DETAILSPLACEHOLDER127

📊 Step Details

Step 1: CYP3A4 ✅

Original New Change
0.038089 0.034567 -0.003522 ↓ 
O=C1NC(=Cc2nc(=O)cc(N3CCOCC3)[nH]2)C(=O)S1

Step 2: PGP ✅

Original New Change
0.755234 0.621777 -0.133457 ↓ 
CC(C)COc1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

Step 3: PGP ⚠️

Original New Change
0.621777 0.627767 +0.005990 ↓ 
CC1(C)c2[nH]nc(N3Cc4c(C(=O)Cc5cccs5)n[nH]c4C3(C)C)c2CN1C=C1NC(=O)SC1=O

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.476903 0.314900 -0.162003 +0.3397 -33.97% ✅ Improved
BBBP ↑ higher 0.999998 0.999992 -0.000006 -0.0000 -0.00% ❌ Declined
CYP3A4 ↓ lower 0.038089 0.006490 -0.031599 +0.8296 -82.96% ✅ Improved
DILI ↓ lower 0.767693 0.495032 -0.272661 +0.3552 -35.52% ✅ Improved
HIA ↑ higher 0.999400 0.999245 -0.000155 -0.0002 -0.02% ❌ Declined
PGP ↓ lower 0.680634 0.627767 -0.052867 +0.0777 -7.77% ✅ Improved

Improved: 4/6 (66.7%) | Molecules: 55 | Paths: 94

🔍 Safety Threshold Analysis

Status: 3/6 meet thresholds

⚠️ Below threshold: 3

Task Score Threshold Gap
PGP 0.6278 ↓ 0.3 0.3278
DILI 0.4950 ↓ 0.4 0.0950
AMES 0.3149 ↓ 0.3 0.0149

✅ Passing: 3

Task Score Threshold
BBBP 1.0000 ↑ 0.5
CYP3A4 0.0065 ↓ 0.55
HIA 0.9992 ↑ 0.2

Slide 21: Taranabant (MK-0364)

Initial Task: DILI

SMILES: C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F

❌ Optimization Failed for Taranabant (MK-0364)

No valid paths found. The optimization could not generate any improved molecules.

📊 Initial Molecule Scores

Input SMILES: C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F

Reason: All generated molecules had worse scores than the initial molecule.

🔧 Recommendations

  1. Increase beams: Try num_beams=7 or num_beams=10 for more diversity
  2. Change initial task: Try a different task as the starting point
  3. Reduce depth: Start with depth=1 to see if single-step improvements work
  4. Check initial molecule: It may already be highly optimized

Slide 22: NYX-059

Initial Task: BBBP

SMILES: CC(C)(C)[N+]([O-])=Cc1ccc(cc1S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+]

NYX-059 - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC(C)(C)[N+]([O-])=Cc1ccc(cc1S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+]`
**QED (Drug-likeness):** 0.1268 **Number of Blocks:** 3
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
28 		**Final Optimized** `Cc1occc1-c1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C`
**QED (Drug-likeness):** 0.8142 (+0.6874) ✅ **Number of Blocks:** 3 (+0) ➡️ **Total Block Changes:** 7
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
29

Optimization Steps:

DETAILSPLACEHOLDER130

After (Step 1)

Cn1cc(C=C2NC(=O)SC2=O)c2ccccc21

QED: 0.7995 (+0.6727) ✅

Number of Blocks: 2 (-1) ↓

Block Changes: 4 (+2, -2)

BBBP Score: 0.001933 → 0.998710 (+0.996778)

DETAILSPLACEHOLDER131

DETAILSPLACEHOLDER132

After (Step 2)

O=C1NC(=CC=C2NC(=O)SC2=O)C(=O)S1

QED: 0.6715 (-0.1280) ❌

Number of Blocks: 2 (+0) ➡️

Block Changes: 1 (+0, -1)

AMES Score: 0.324786 → 0.209113 (-0.115673)

DETAILSPLACEHOLDER133

DETAILSPLACEHOLDER134

After (Step 3)

Cc1occc1-c1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

QED: 0.8142 (+0.1427) ✅

Number of Blocks: 3 (+1) ↑

Block Changes: 2 (+2, -0)

PGP Score: 0.676219 → 0.583655 (-0.092563)

DETAILSPLACEHOLDER135

📊 Step Details

Step 1: BBBP ✅

Original New Change
0.001933 0.998710 +0.996778 ↑ 
Cn1cc(C=C2NC(=O)SC2=O)c2ccccc21

Step 2: AMES ✅

Original New Change
0.324786 0.209113 -0.115673 ↓ 
O=C1NC(=CC=C2NC(=O)SC2=O)C(=O)S1

Step 3: PGP ✅

Original New Change
0.676219 0.583655 -0.092563 ↓ 
Cc1occc1-c1n[nH]c2c1CN(C=C1NC(=O)SC1=O)C2(C)C

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.531967 0.609732 +0.077765 -0.1462 +14.62% ❌ Declined
BBBP ↑ higher 0.001933 0.002764 +0.000832 +0.4304 +43.04% ✅ Improved
CYP3A4 ↓ lower 0.000120 0.004026 +0.003907 -32.6844 +3268.44% ❌ Declined
DILI ↓ lower 0.483893 0.741515 +0.257622 -0.5324 +53.24% ❌ Declined
HIA ↑ higher 0.994940 0.996004 +0.001064 +0.0011 +0.11% ✅ Improved
PGP ↓ lower 0.765508 0.583655 -0.181853 +0.2376 -23.76% ✅ Improved

Improved: 3/6 (50.0%) | Molecules: 133 | Paths: 300

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0028 ↑ 0.5 0.4972
DILI 0.7415 ↓ 0.4 0.3415
AMES 0.6097 ↓ 0.3 0.3097
PGP 0.5837 ↓ 0.3 0.2837

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0040 ↓ 0.55
HIA 0.9960 ↑ 0.2

Slide 23: AZD-3514

Initial Task: HIA

SMILES: CC(=O)N1CCN(CC1)CCOC2=CC=C(C=C2)C3CCN(CC3)C4=NN5C(=NN=C5C(F)(F)F)CC4

AZD-3514 - Optimization Results

🔗 Optimization Path

📊 Overall Comparison - Initial → Final

**Initial Molecule** `CC(=O)N1CCN(CC1)CCOC2=CC=C(C=C2)C3CCN(CC3)C4=NN5C(=NN=C5C(F)(F)F)CC4`
**QED (Drug-likeness):** 0.6048 **Number of Blocks:** 4
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
36 		**Final Optimized** `CC(C)(OC(=O)C(C)(C)OC1=Nn2c(nnc2C(F)(F)F)CC1)C(=O)NCc1ccc(/C(N)=N\O)cc1`
**QED (Drug-likeness):** 0.1621 (-0.4427) ❌ **Number of Blocks:** 3 (-1) ↓ **Total Block Changes:** 9
▶ Show ADMET Scores
Task Score Change Rel. Improvement % Change
AMES ❌ 0.686654 +0.267605 -0.6386 +63.86%
BBBP ❌ 0.000213 -0.777801 -0.9997 -99.97%
CYP3A4 ✅ 0.000889 -0.011059 +0.9256 -92.56%
DILI ✅ 0.659112 -0.134808 +0.1698 -16.98%
HIA ✅ 0.997891 +0.013316 +0.0135 +1.35%
PGP ❌ 0.556859 +0.057154 -0.1144 +11.44%
37

Optimization Steps:

DETAILSPLACEHOLDER138

After (Step 1)

CC(=O)N1CCN(CCOC(=O)C(C)(C)OC2CCN(CC3=Nn4c(nnc4C(F)(F)F)CC3)CC2)CC1

QED: 0.4537 (-0.1511) ❌

Number of Blocks: 3 (-1) ↓

Block Changes: 3 (+1, -2)

HIA Score: 0.999712 → 0.999154 (-0.000558)

DETAILSPLACEHOLDER139

DETAILSPLACEHOLDER140

After (Step 2)

CC(C)(OC1CCN(CC2=Nn3c(nnc3C(F)(F)F)CC2)CC1)C(=O)NCc1ccc(/C(N)=N\O)cc1

QED: 0.2030 (-0.2507) ❌

Number of Blocks: 3 (+0) ➡️

Block Changes: 2 (+1, -1)

AMES Score: 0.396480 → 0.731145 (+0.334666)

DETAILSPLACEHOLDER141

DETAILSPLACEHOLDER142

After (Step 3)

CC(C)(OC(=O)C(C)(C)OC1=Nn2c(nnc2C(F)(F)F)CC1)C(=O)NCc1ccc(/C(N)=N\O)cc1

QED: 0.1621 (-0.0408) ❌

Number of Blocks: 3 (+0) ➡️

Block Changes: 4 (+2, -2)

AMES Score: 0.731145 → 0.641817 (-0.089329)

DETAILSPLACEHOLDER143

📊 Step Details

Step 1: HIA ⚠️

Original New Change
0.999712 0.999154 -0.000558 ↑ 
CC(=O)N1CCN(CCOC(=O)C(C)(C)OC2CCN(CC3=Nn4c(nnc4C(F)(F)F)CC3)CC2)CC1

Step 2: AMES ⚠️

Original New Change
0.396480 0.731145 +0.334666 ↓ 
CC(C)(OC1CCN(CC2=Nn3c(nnc3C(F)(F)F)CC2)CC1)C(=O)NCc1ccc(/C(N)=N\O)cc1

Step 3: AMES ✅

Original New Change
0.731145 0.641817 -0.089329 ↓ 
CC(C)(OC(=O)C(C)(C)OC1=Nn2c(nnc2C(F)(F)F)CC1)C(=O)NCc1ccc(/C(N)=N\O)cc1

📊 ADMET Comparison

Task Direction Initial Final Change Rel. Improvement % Change Status
AMES ↓ lower 0.382188 0.641817 +0.259629 -0.6793 +67.93% ❌ Declined
BBBP ↑ higher 0.998411 0.000596 -0.997815 -0.9994 -99.94% ❌ Declined
CYP3A4 ↓ lower 0.030133 0.019928 -0.010205 +0.3387 -33.87% ✅ Improved
DILI ↓ lower 0.747011 0.551265 -0.195746 +0.2620 -26.20% ✅ Improved
HIA ↑ higher 0.999712 0.938515 -0.061197 -0.0612 -6.12% ❌ Declined
PGP ↓ lower 0.644132 0.620027 -0.024105 +0.0374 -3.74% ✅ Improved

Improved: 3/6 (50.0%) | Molecules: 31 | Paths: 102

🔍 Safety Threshold Analysis

Status: 2/6 meet thresholds

⚠️ Below threshold: 4

Task Score Threshold Gap
BBBP 0.0006 ↑ 0.5 0.4994
AMES 0.6418 ↓ 0.3 0.3418
PGP 0.6200 ↓ 0.3 0.3200
DILI 0.5513 ↓ 0.4 0.1513

✅ Passing: 2

Task Score Threshold
CYP3A4 0.0199 ↓ 0.55
HIA 0.9385 ↑ 0.2